It has recently become apparent based upon both metabolic and immunologic data that insulin dependent diabetes (IDD) as a disease process usually begins years before the detection of clinical IDD and that insulin secretory capacity must be markedly impaired before hyperglycemia occurs. Several immunologic abnormalities are present in IDD at diagnosis and when evaluated some have also been found to be present in individuals years before the onset of clinical IDD. One of these, islet cell antibodies (ICA), has been proposed as a marker of active beta cell damage but several lines of evidence suggest that ICA may not be specific for IDD. We have recently found that 30-40% of newly diagnosed insulin dependent diabetics prior to insulin treatment have insulin antibodies and have suggested that this may serve as a more specific marker of pre-clinical IDD. Since the end result of IDD as a disease process is severe insulin deficiency and the decline in beta cell function takes place over an extended period of time prior to clinical IDD, we propose that careful investigation of the pattern of decline in beta cell function using very sophisticated function tests may provide the clearest indication for etiologic heterogeneity of IDD. In the studies described in this application we propose to screen a large number of siblings of insulin dependent diabetics, using islet cell antibodies and insulin antibodies as the markers, to identify fifty positive individuals who will then be studied both cross-sectionally and longitudinally. By careful quantification of beta cell function the predictive value of ICA and insulin antibodies as markers of beta cell dysfunction will be tested, and the prevalence of and severity of the beta cell abnormality in these individuals will be determined. By performing the beta cell function tests at repeated intervals over several years in these individuals we also propose to test the hypothesis that beta cell injury in pre-clinical IDD is not always a steady progressive process but may be intermittent and probably cumulative. Specifically we will evaluate the sequential tests of beta cell function to determine whether the decline is progressive or whether it is intermittent separated by periods of stable beta cell function and/or recovery. And finally we propose to employ the identical cell function tests in baboons before and after sequential doses of streptozotocin. By carefully quantifying the degree of beta cell destruction after sacrifice we will be able to determine whether the abnormalities in beta cell function that we expect to find in ICA and/or insulin antibody positive siblings are indicative of beta cell destruction and/or whether any are due to beta cell recovery or regeneration.